Genetic Variant NHSL3:p.Pro22Leu (chr1-32742019-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020888.3(NHSL3):c.65C>T(p.Pro22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000323 in 1,239,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P22Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

NHSL3
NM_020888.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.223

Publications

0 publications found

Variant links:

Genes affected

NHSL3 (HGNC:29301): (NHS like 3) Predicted to be involved in cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

NHSL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.053604007).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020888.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHSL3	NM_020888.3	MANE Select	c.65C>T	p.Pro22Leu	missense	Exon 1 of 7	NP_065939.2	Q9P206-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NHSL3	ENST00000401073.7	TSL:2 MANE Select	c.65C>T	p.Pro22Leu	missense	Exon 1 of 7	ENSP00000383851.2	Q9P206-2
NHSL3	ENST00000963202.1		c.65C>T	p.Pro22Leu	missense	Exon 1 of 6	ENSP00000633261.1
NHSL3	ENST00000963201.1		c.65C>T	p.Pro22Leu	missense	Exon 1 of 5	ENSP00000633260.1

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1088640

Hom.:

Cov.:

AF XY:

0.00000193

AC XY:

AN XY:

518830

show subpopulations

African (AFR)

AF:

0.0000443

AC:

AN:

22566

American (AMR)

AF:

0.00

AC:

AN:

10118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15122

East Asian (EAS)

AF:

0.00

AC:

AN:

25644

South Asian (SAS)

AF:

0.00

AC:

AN:

25282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21868

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2950

European-Non Finnish (NFE)

AF:

0.00000217

AC:

AN:

921706

Other (OTH)

AF:

0.00

AC:

AN:

43384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150808

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73620

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41234

American (AMR)

AF:

0.00

AC:

AN:

15160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67596

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.51

M_CAP

Benign

0.080

MetaRNN

Benign

0.054

MetaSVM

Benign

-1.0

PhyloP100

0.22

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.9

REVEL

Benign

0.021

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.032

Polyphen

0.0

Vest4

0.14

MutPred

0.23

Loss of glycosylation at P22 (P = 0.0079)

MVP

0.043

MPC

0.12

ClinPred

0.60

GERP RS

0.038

PromoterAI

0.039

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.25

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over